In vivo supramolecular templating enhances the activity of multivalent ligands: a potential therapeutic against the Escherichia coli O157 AB5 toxins.
We demonstrate that interactions between multimeric receptors and multivalent ligands are dramatically enhanced by recruiting a complementary templating receptor such as an endogenous multimeric protein but only when individual ligands are attached to a polymer as preorganized, covalent, heterobifunctional pairs. This effect cannot be replicated by a multivalent ligand if the same recognition elements are independently arrayed on the scaffold. Application of this principle offers an approach to create high-avidity inhibitors for multimeric receptors. Judicious selection of the ligand that engages the templating protein allows appropriate effector function to be incorporated in the polymeric construct, thereby providing an opportunity for therapeutic applications. The power of this approach is exemplified by the design of exceptionally potent Escherichia coli Shiga toxin antagonists that protect transgenic mice that constitutively express a human pentraxin, serum amyloid P component.
Kitov
Pavel I
PI
Department of Chemistry, Alberta Ingenuity Centre for Carbohydrate Science, University of Alberta, Edmonton, AB, Canada T6G 2G2.
Mulvey
George L
GL
Griener
Thomas P
TP
Lipinski
Tomasz
T
Solomon
Dmitry
D
Paszkiewicz
Eugenia
E
Jacobson
Jared M
JM
Sadowska
Joanna M
JM
Suzuki
Missao
M
Yamamura
Ken-Ichi
K
Armstrong
Glen D
GD
Bundle
David R
DR
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D019453:Escherichia coli O157 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000683:Serum Amyloid P-Component / Q000378:metabolism; D022622:Shiga Toxin 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry
D000900:Anti-Bacterial Agents; D008024:Ligands; D011108:Polymers; D000683:Serum Amyloid P-Component; D022622:Shiga Toxin 1